ABSTRACT: This proposal aims to elucidate the functional organization of the whole brain in Autism Spectrum Disorders (hereafter referred to as autism), a group of neurodevelopmental disorders that affect roughly 1 in 110 individuals born today. I will test the overarching hypothesis that functional coupling between different regions of the brain in autism is generally reduced. Moreover, I will explore the prediction that such reduced connectivity is associated with abnormal behavior. While anatomical and functional evidence support reduced brain connectivity in autism, this has never been tested at the whole-brain level. In this application, I propose to acquire resting-state and stimulus-evoked Blood Oxygenation Level Dependent (BOLD) activity across the entire brain in high-functioning adults with autism and matched healthy control participants. A measure of functional connectivity will be derived from the resting-state BOLD activity, by examining the functional coupling across all regions of the brain in a pairwise manner. In each of 4 specific aims, I will test the following hypotheses: (1) that the autistic brain is generally less connected than normal, but that there is anatomical specificity to this reduction, (2) that the functional responsivity of the entire brain can be examined simultaneously in autism using complex naturalistic stimuli, and can be used to reveal which regions function abnormally in autism, (3) that abnormal resting-state functional connectivity is associated with reduced evoked activity in those same regions, and (4) that the functional properties of broadly distributed brain regions contain information that can be used to predict a diagnosis of autism. Aims 1 & 2 will be carried out during the training phase (K99) of the grant, while Aims 3 & 4 will be completed during the independent phase (R00). The training component will consist of learning state-of-the-art functional imaging methods at the Caltech Brain Imaging Center, together with statistical techniques for pattern classification. Together, these studies will provide the first comprehensive picture of brain connectivity and brain activity in autism, and set the direction for my future career.